Insulin and new oral hypoglycaemics

Dr R Banerjee MD FRCP Consultant Endocrinologist Luton & Dunstable Hospital

23rd March 2011, Lister Hospital

Pharmacological treatments for Diabetes Mellitus

Dr R Banerjee MD FRCP Consultant Endocrinologist Luton & Dunstable Hospital

23rd March 2011, Lister Hospital

What shall we cover?

•  Insulin •  Oral Hypoglycaemics •  Others/Newer agents

...but not in this order!

Justify (Insulin and new oral hypoglycaemics ....... Pharmacological treatments for Diabetes Mellitus)

Previously

Injections - insulin Non-insulin treatment - oral

Nomenclature IDDM and NIDDM

Pharmacological approach

Regulation of glucose

1-food 2-GIP release 3-β cells 4/5/6-inhibitory 7-incretin effect

Classification •  Insulin sensitisers •  Insulin secreatgogoues •  Alpha glucosidase inhibitors •  Amylin analogues •  SGLT-2 inhibitors •  Insulins •  Incretins/Gliptins

Insulin sensitisers

•  Biguanides

•  PPARγ agonist/Thiazolidinedione

•  Dual PPAR agonist (α and γ)

Insulin sensitisers

•  Biguanides

– Metformin » Hepatic glucose output »  Skeletal muscle uptake

–  Phenformin

•  PPARγagonist/Thiazolidinediones

•  Dual PPAR agonist (α and γ)

Insulin sensitisers

•  Biguanides •  PPARγ agonist/Thiazolidinediones

–  Pioglitazone – Rosiglitazone/Troglitazone

•  Dual PPAR agonist (α and γ) –  Aleglitazar

– γ : adipose tissue, βcells,vascular endoth, macrophages

– α : liver, heart, skeletal muscle, vascular wall

Classification

•  Insulin sensitisers •  Insulin secreatgogoues •  Alpha glucosidase inhibitors •  Amylin analogues •  SGLT-2 inhibitors •  Insulins •  Incretins/Gliptins

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Insulin secretagogues

ATP sensitive potassium channels

•  Sulfonylureas

•  Meglitinides

Insulin secretagogues

ATP sensitive potassium channels

•  Sulfonylureas –  1st gen –  2nd gen –  3rd gen?

•  Meglitinides

√√√√

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**

Insulin secretagogues

ATP sensitive potassium channels

•  Sulfonylureas

•  Meglitinides (prandial glucose regulators) – Repaglinide – Nateglinide

Classification •  Insulin sensitisers •  Insulin secreatgogoues •  Alpha glucosidase inhibitors •  Amylin analogues •  SGLT-2 inhibitors •  Insulins •  Incretins/Gliptins

√ √

Alpha gucosidase inhibitor

•  Acarbose •  Voglibose •  Miglitol

•  Prevents carbohydrate digestion (complex poly to mono) •  Also blocks pancreatic alpha amylase

•  SE •  Treatment of hypoglycaemia •  Use with caution in severe renal impairment

Classification •  Insulin sensitisers •  Insulin secreatgogoues •  Alpha glucosidase inhibitors •  Amylin analogues •  SGLT-2 inhibitors •  Insulins •  Incretins/Gliptins

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Amylin analogues

Amylin analogues

•  Pramlintide •  Same as insulin •  Works by

•  slowing gastric emptying •  regulation of post prandial glucose •  reduction of food intake/increasing satiety -(wt

loss)

Classification •  Insulin sensitisers •  Insulin secreatgogoues •  Alpha glucosidase inhibitors •  Amylin analogues •  SGLT-2 inhibitors •  Insulins •  Incretins/Gliptins

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SGLT-2 inhibitors

•  Sodium dependent glucose cotransporters •  SGLT1: sm intestinal mucosa •  SGLT2 (and 1): proximal tubule of nephron

•  90% of glucose reabsorption

–  Canagliflozin –  Dapagliflozin

Classification •  Insulin sensitisers •  Insulin secreatgogoues •  Alpha glucosidase inhibitors •  Amylin analogues •  SGLT-2 inhibitors •  Insulins •  Incretins/Gliptins

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Back to basic...

Insulin

Insulins

•  Rapids •  Intermediates •  Long

•  Humalog lispro •  Humalog mix25 •  Humalog mix50 •  Humulin I •  Humulin S •  Humulin M3

•  Lantus(glargine)

•  Novorapid •  Novomix30

•  Insulatard •  Actrapid •  Mixtard 30

•  Levemir (detemir)

Available insulins

•  Rapids –  Human (Actrapid/HumulinS) –  Analogues (Novorapid, Humalog Lispro, Glulisine) –  Inhaled insulin (exubera)

•  Intermediate –  Insulatard/Humulin I –  Premixed (Mixtard30/Humulin M3/Novomix30/

Mumalog mix25 and mix50) •  Long

–  Glargine –  Detemir –  Degludec (trial)

Normal

Classification •  Insulin sensitisers •  Insulin secreatgogoues •  Alpha glucosidase inhibitors •  Amylin analogues •  SGLT-2 inhibitors •  Insulins •  Incretins/Gliptins

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Incretins/Gliptins

Incretins/Gliptins

Incretins are a group of gastrointestinal hormones that cause an increase in the amount of insulin released from the beta cells of the islets of Langerhans after eating, even before blood glucose levels become elevated

Eg. Gastric-inhibitory-peptide (GIP), Glucagon-like-peptide1(GLP1)

Incretin effect after oral glucose was diminished in type 2 diabetes6

*p£0.05 vs. respective value after oral load IR=immunoreactive 6. Adapted from Nauck M et al Diabetologia 1986;29:46–52.

Diminished incretin effect

Normal incretin effect

Oral glucose (50 g/400 ml) Isoglycaemic intravenous glucose

0 –10

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Healthy controls (n=8) Type 2 diabetes (n=14)

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–10 60 120 180 –5 –10 60 120 180 –5

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Oral/Intravenous Glucose Infusion Study

Why are incretins important?

•  Incretins are important : –  The “incretin effect” –  The incretin effect accounts for ~60% of total

insulin release following a meal •  Incretin effect is due to Incretins (hormones)

secreted by intestinal endocrine cells in response to nutrient intake

•  Accessory effects..

Adapted from 1Nauck MA, et al. Diabetologia 1993;36:741–744; 2Larsson H, et al. Acta Physiol Scand 1997;160:413–422; 3Nauck MA, et al. Diabetologia 1996;39:1546–1553; 4Flint A, et al. J Clin Invest 1998;101:515–520; 5Zander et al. Lancet 2002;359:824–830.

GLP-1 secreted upon the ingestion of food

1.β-cell: Enhances glucose-dependent

insulin secretion in the pancreas1

3.Liver: reduces hepatic glucose

output2

2.α-cell: Suppresses postprandial

glucagon secretion1

4.Stomach: slows the rate of gastric emptying3

5.Brain: Promotes satiety and

reduces appetite4,5

Natural role of incretins

Incretins and glycaemic control7,8

Adapted from 7. Drucker DJ. Cell Metab. 2006;3:153–165. 8. Miller S, St Onge EL. Ann Pharmacother 2006;40:1336-1343.

Active GLP-1 and GIP

Release of incretin gut hormones

Pancreas

Blood glucose control

GI tract

ä  Glucagon from alpha cells

(GLP-1) Glucose

dependent

Alpha cells

Increased insulin and decreased glucagon reduce hepatic glucose output

Glucose dependent é  Insulin

from beta cells (GLP-1 and GIP)

Beta cells

Insulin increases peripheral glucose uptake

Ingestion of food

DPP-4 enzyme rapidly

degrades incretins

Mode of action of DPP-4 inhibitor

Adapted from 8. Miller S, St Onge EL. Ann Pharmacother 2006;40:1336-1343.

A DPP-4 inhibitor and inhibits the

breakdown of incretins and thereby

increases active incretin levels

DPP-4= dipeptidyl peptidase 4 inhibitor

Active GLP-1 and GIP

Release of incretin gut hormones

Pancreas

Blood glucose control

GI tract

ä  Glucagon from alpha cells

(GLP-1) Glucose

dependent

Alpha cells

Increased insulin and decreased glucagon reduce hepatic glucose output

Glucose dependent é  Insulin

from beta cells (GLP-1 and GIP)

Beta cells

Insulin increases peripheral glucose uptake

Ingestion of food

DPP-4 enzyme rapidly

degrades incretins

1Wei Y, et al. FEBS Lett 1995;358:219–224; 2Drucker DJ. Diabetes Care 2003;26:2929–2940.

GLP-1 GIP 30 amino acid peptide1 42 amino acid peptide2

Synthesised and released by L cells of ileum and colon

Synthesised and released from K cells of jejunum and duodenum

Sites of action: Pancreatic β-cells and α-cells GI tract CNS Lungs Heart

Sites of action: Pancreatic β-cells Adiopocytes

Two main incretins...

GLP1 mimetics •  Exenetide •  Exenetide LAR •  Liraglutide •  Taspoglutide •  Albiglutide

GLP 1 enhancers (DPP-4 Inhibitor) •  Sitagliptin •  Vildagliptin •  Saxagliptin •  Linagliptin •  Algoliptin

(S/C Inj)

(Oral)

Incretin based therapies

GLP-1 effects

Mean (SE); N = 10; *P < 0.05. Nauck MA, et al. Diabetologia 1993;36:741–744.

Glu

cago

n (p

mol

/L) 300

200

100

0

Insu

lin (p

mol

/L)

Time (min) -30 0 60 120 180 240

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cose

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PBO GLP-1

PBO GLP-1

PBO GLP-1

Placebo (PBO) GLP-1

GLP1 mimetics

•  Exenatide/Liraglutide

Does it work?

82-wk completers; Mean (SE); Weight was a secondary endpoint Adapted from Blonde L, et al. Poster presented at the American Diabetes Association Meeting 2005 (Abstract 477P)

Baseline body weight 98 kg

100 kg 100 kg

0 10 20 30 40 50 60 70 80 90 -5

-4

-3

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-1

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Mea

n ∆

body

wei

ght (

kg)

Placebo BD (N = 128) Exenatide 5 µg BD (N = 128) Exenatide 10 µg BD (N = 137)

Open-label extension (all patients exenatide 10 µg BD)

Placebo-controlled Trials

Time (week)

1

Open-label extension study – combined 82-week completers data. Exenatide continued to reduce weight

-1.1% -1.1%

-1.5

-1.0

-0.5

0.0

% C

hang

e in

HbA

1c

HbA1c <7% HbA1c <6.5%

46% 48%

32% 25%

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20

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% P

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Exenatide Insulin glargine

ITT population; Mean ± SE shown. Heine RJ et al. Ann Intern Med. 2005;143:559-569.

(n=275) (n=260)

(Pts on Exenatide were better off by 5-6 kg)

Exenatide vs. Insulin Glargine Comparator Trial: Achieved Equivalent Reductions in HbA1c

Exenatide 5 µg Placebo and 10 µg BD

(N = 483) (N = 963)

Nausea 18% 44% Vomiting 4% 13% Diarrhoea 6% 13% Feeling jittery 4% 9% Dizziness 6% 9% Headache 6% 9% Dyspepsia 3% 6%

Overall incidence ≥5% and incidence of Exenatide > placebo BYETTA® (exenatide) US Prescribing Information, February 2007, data on file.

Results of 30-week exenatide studies

Adverse events

GLP1 mimetics

•  Exenatide/Liraglutide •  Caution in Cr Cl <50 ml/min (not used <30) •  SEs: Nausea/vomting. Pancreatitis* •  Wt reduction •  Papillary thyroid/Thyroid C cell hyperplasia

(Liraglutide)

GLP1 enhancers

•  Sitagliptin/Vildagliptin/Saxagliptin

Does it work?

•  Sitagliptin –  Monotherapy

•  0.6% reduction in HbA1c •  -1.5% if starting >9%

–  Combined •  +metformin: -0.6% •  +pioglitazone: -0.85% •  Sitagliptin+metformin vs glipizide+ metformin: 0.7% in

both but hypo in glipizide group

•  Functions as tumour suppressor •  Adjust dose in renal compromise

•  Saxagliptin/Vildagliptin/Sitagliptin •  Same efficacy overall •  Abdo pain/nausea/vomiting common •  Pancreatitis •  Skin reaction •  Vildagliptin - hepatic dysfunction •  Renal safety - ? Saxagliptin •  Weight neutral

Incretins/Gliptins

•  Not as monotherapy •  Not with insulin •  Third agent or second agent

Classification •  Insulin sensitisers •  Insulin secreatgogoues •  Alpha glucosidase inhibitors •  Amylin analogues •  SGLT-2 inhibitors •  Insulins •  Incretins/Gliptins

√ √ √ √

√ √

√

Conclusion: we covered

•  Insulin •  Oral Hypoglycaemics •  Others/Newer agents

...but not in that order!

Summary

•  Will see various combinations of insulin therapy

•  Will see various combinations of agents, oral and injections

•  Be aware of new side effects for the newer agents

•  Pump - still not widely available •  Transplant/artificial pancreas ......